Hepatitis E: an overview. Harry Dalton. European Centre for Environment & Human Health University of Exeter Medical School Cornwall, UK

Transcription

1 Hepatitis E: an overview Harry Dalton European Centre for Environment & Human Health University of Exeter Medical School Cornwall, UK

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3 Talk outline HEV: Acute & chronic infection Places HEV hides: History books Population level Patient level Speculation: Pork Consumption and liver deaths

4 HEV RNA virus Genotypes 1 & 2: human disease only waterborne Genotype 3 (& 4): Human disease Found in animals (asymptomatic) Pigs Worldwide 85% UK pigs affected Boar, deer, rabbits Rats, ferrets, bats, cut-throat trout, mongoose

5 HEV in developing countries Major health issue Large outbreaks Genotypes 1 & 2 Faeco-oral route via infected water Affects young adults Mortality in pregnant women 25%

6 HEV: in chronic liver disease Kumar Acharya et al J Hepatol 2007

7 HEV in developed countries: received wisdom A bit like HAV Acute illness Self-limiting Mainly seen in travellers v. rare in nontravellers Of little relevance in developed countries

8 HEV in developed countries: received wisdom A bit like HAV Acute illness Self-limiting Mainly seen in travellers v. rare in nontravellers Of little relevance in developed countries

9 Cornwall Good location to do epidemiological studies <0.5% immigrants

10 Jaundice hotline clinic: (n > 2,300) Diagnoses in over 60's CBD stones pancreatic/biliary cancer decompensated chronic liver disease/alcohol metastatic cancer drug-induced liver injury miscellaneous unknown

11 Acute HEV3: clinical features 73 cases of HEV in non-travellers 58/73 HEV PCR +ve, all genotype 3 M:F = 3:1 Median age 63.5 years (range 32-92) Dalton et al J Viral Hepatitis 2007 Dalton et al EurJGastro 2008 Vine et al APT 2012

12 Acute HEV3: symptoms Dalton et al EJGH 2008 Jaundice (n=44) Anorexia (n=27) Lethargy (n=27) Abdo pain (n=25) Vomiting (n=12) Fever (n=12) Myalgia (n=11) Pruritis (n=10) Weight loss (n=7) Headaches (n=6) Arthralgia (n=6) Neurological (n=7) No symptoms (n=3)

13 Acute HEV3: Spectrum of severity Asymptomatic mild hepatitis liver failure Most recover 4-6 weeks 70% mortality in patients with pre-existing chronic liver disease Dalton et al Lancet 2007 Peron et al JViralHepat 2007

14 HEV: Other developed countries USA Halbur JClinMicro 2001 Japan Miuzo ClinMicro 2002 France Mansuy JMedVirol 2004 Netherlands Widdowson JMedVirol 2004 Spain Buti JVirolMethods 1995 Italy Romano J Hepatol 2010 New Zealand Dalton JGastHepatol 2007 Denmark, Germany, Hungary, Sweden

15 HEV: demographics and outcome UK France Japan Dalton et al 2008 Peron et al 2006 Okamoto et al 2003 Cases Mean age 65 yrs 54.4 yrs 59.6 yrs % males 77.5% 73.9% 87% Deaths 7.5% 8.7% 10.8% Liver deaths 5% 8.7% 10.8%

16 HEV3: incidence More common than HAV Dalton et al EuroJClinMicro 2008 Vine et al AlimentPharmacol Therap 2012 Geographical variation: UK: 0.2% Ijaz et al 2009 JClinVirol USA: 0.7% = > 2 million infections per year Faramwi et al EpidInfect 2011

17 HEV 3: Asymptomatic infection Asymptomatic infection probably very common Aurora outbreak cases hepatitis E 67% asymptomatic Said et al EmInfDis 2009

18 HEV3: Source and route of infection

19 Chronic HEV infection: Transplant recipients Chronic HEV3 infection in transplant patients Kamar et al NEJM 2008 No symptoms, anicteric, ALT IU/L Chronicity occurs in 60% of HEV3 infections Tacrolimus Low platelet count Kamar et al Gastroenterology 2011 Cirrhosis rapidly progressive Kamar et al Transplant 2010 Very high incidence of chronic HEV in French transplant centres Prevalence in other European transplant centres: 1-2%

20 Chronic HEV infection: HIV 48-yr old bisexual male, alcohol ++ HIV-1 since 2001, SE Asia TB treated 2003 Anti-retroviral therapy started 2007 CD4: 30 cells/mm 3 viral load: copies/ml LFT s abnormal, neurological symptoms?drug reaction Chronic HEV3 infection Dalton et al NewEngJMed 2009

21 HEV & HIV co-infection Small number of cases in Europe 5 chronic HEV, 2 cirrhotic CD4 counts <250 Dalton et al NewEngJMed 2009 Colson et al J Viral Hepatitis 2011 Foguena et al Emerg Infec Dis 2011 Kaba et al J Med Virol 2011 Jagjit Singh et al J Infection 2012 No evidence of sexual transmission Keane et al 2012, HIV Med

22 HEV & HIV chronic co-infection: potential burden of disease

23 Places HEV hides:

24 Places HEV hides (1): history books HEV as an emerging disease Old disease Diverged into 4 genotypes 18 th Century 19 th Century HEV1 common in Europe HEV1 moved east (Asia) and south (Africa) Teo EpidemiolInfect 2012 HEV3 hid in pigs, only recently recognised

25 Places HEV hides (2): at population level

26 HEV serology Poor concordance between assays IgG assays particularly problematic

27 HEV IgG seroprevalence in developed countries 9.2% 5.3% 20% 5.2% 16% Map Country Key UK 16% New Zealand 4% Denmark 20.6% Tokyo 3% 8 US States 18.3% Moldova 24.7% Iowa 3.3% New York 31% California 13.7% Baltimore 21.3% SW France 16.6% Northern France 3.2% Catalonia 7.3% Australia 0.4% Holland 1% Austria 3% Greece 0.26% Sweden 9.2% San Marino 1.5% Madrid 2.8% Stockholm 5.2% Calabria/Italy 1.7% UK 5.3% Barcelona 5.5% Switzerland 3.2% Italy 1.2% Holland 1.1% 13.7% 3.3% 18.3% 21% 31% 2.8% 3% 3% 16% 7.3% 1.5% 25% 0.2% 3% 0.4% 4%

28 HEV IgG seroprevalence in developed countries 16% 3% 16% Key Genelabs assay Wantai assay

29 Wantai vs Genelabs HEV IgG assay Bendall et al J Med Virol 2010 PCR proven HEV3 cases (n=18) Serial samples n=50 (up to 7 years) Genelabs underestimates true seroprevalence by a factor of 4 Toulouse study showed seroprev of 16% using Genelabs

30 HEV IgG seroprevalence in developed countries 16% Key Genelabs assay 3% 52% Wantai assay 4%

31 52%!!!!!!! Seroprevalence in children aged 2-4 years = 2% Observed incidence of HEV infection in Toulouse = 3.2% Mansuy et al Emerg Inf Dis 2011

32 HEV IgG seroprevalence in developed countries 9.2% 5.3% 20% 5.2% 16% Map Country Key UK 16% New Zealand 4% Denmark 20.6% Tokyo 3% 8 US States 18.3% Moldova 24.7% Iowa 3.3% New York 31% California 13.7% Baltimore 21.3% SW France 16.6% Northern France 3.2% Catalonia 7.3% Australia 0.4% Holland 1% Austria 3% Greece 0.26% Sweden 9.2% San Marino 1.5% Madrid 2.8% Stockholm 5.2% Calabria/Italy 1.7% UK 5.3% Barcelona 5.5% Switzerland 3.2% Italy 1.2% Holland 1.1% 13.7% 3.3% 18.3% 21% 31% 2.8% 3% 3% 16% 7.3% 1.5% 25% 0.2% 3% 0.4% 4%

33 HEV IgG seroprevalence in developed countries

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35 Places HEV hides (3): at patient level

36 Places HEV hides: with the Neurologist Kamar et al Emerg Inf Dis 2011 HEV is neuropathogenic: inflammatory polyradiculopathy Guillain Barré syndrome bilateral brachial neuritis Encephalitis, Bell s Palsy. ataxia/proximal myopathy, etc LFTs only mildly abnormal and most cases anicteric Occurs in: acute and chronic HEV Developed and developing countries Outcome: Most recover, some do not

37 Places HEV hides: With the Hepatologist: Drug-induced liver injury (DILI) 13% of patients with DILI have HEV3 Dalton et al APTherap 2007 USA: 3% of DILI is HEV3 infection Davern et al Gastroenterol 2011 Diagnosis of DILI not secure without testing for HEV

38 Places HEV hides: with the transplant physician Chronic infection Asymptomatic ALT

39 70 year old male Places HEV hides: with the Cardiologist Anterior MI 15 years previously Presents with ventricular tacchycardia (VT) Successfully cardioverted ALT 1,250, bilirubin 16 Diagnosis: scar-vt with ischaemic hepatitis HEV genotype 3

40 Places HEV hides: blood supply

41 Places HEV hides: patients with decompensated chronic liver disease 76 yr old male Alcohol 35U/week Decompensated +++ Bilirubin 86 ALT 2286 Transferred to another hospital Died at 4 months of decompensated alcoholic liver disease due to alcoholic hepatitis

42 Speculation: Pork consumption & liver deaths

43 Speculation: Pork consumption & liver deaths Deaths from cirrhosis vs ethanol consumption & pork consumption Developed countries (1965, mid 1970 s) Lancet 1985

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45 Mortality from chronic liver disease vs alcohol consumption Dalton et al Epidemiol Infect 2010 R 2 =0.473 p=0.002

46 Mortality from chronic liver disease vs pork consumption R 2 =0.531 p=0.001 R 2 =0.531 p=0.001

47 Multiple regression: Independent predictors of mortality: Alcohol consumption HBV seroprevalence Pig meat consumption (p=0.005) (p=0.037) (p<0.001)

48 Possible explanations: 1. Epiphenomenon 2. A factor in pork causes cirrhosis 3. A factor in pork causes death in patients with pre-existing cirrhosis? HEV3 HEV3 found in retail pig meat» USA, Holland, Japan, UK & France HEV survives cooking at 56C & can be transmitted by eating infected meat HEV mortality in chronic liver disease = 70%

49 HEV: potential mortality in developed countries Assuming: Prevalence of chronic liver disease = 1% Mortality HEV in chronic liver disease = 70% Population of USA, Canada, EU, Japan, Australia & NZ = 931million Annual HEV seroconversion rate = 0.2% 13,000 deaths/annum attributable to HEV infection in patients with chronic liver disease

50 HEV in developed countries: received wisdom A bit like HAV Acute illness Self-limiting Mainly seen in travellers v. rare in nontravellers Of little relevance in developed countries

51 Conclusions: HEV in developed countries Common Zoonosis HEV likes to hide Significant morbidity & mortality Prognosis poor in chronic liver disease May cause up to 13,000 deaths per year

52 Acknowledgments Lemon Street Gallery, Truro Sheila Sherlock Travelling Bursary 2011 Office of Chief Scientist Scotland Duchy Charity

53 research collaborators Colleagues in SW England: Dr Richard Bendall Dr Frances Keane (Truro), Dr Mark Gompels (Bristol) UK, national: Malcolm Banks: Veterinary Laboratory Association (Surrey) Linda Scobie: Glasgow Caledonian University, Scotland Adrian Stanley: Glasgow Royal Infirmary Prof Richard Tedder, Dr Samreen Ijaz: Health Protection Agency (London) Ellie Barnes: University of Oxford International: Bob Purcell/Sue Emerson, NIH, Bethesda, Maryland, USA Hans Zaaijer and Bart Jacobs, The Netherlands Alessandro Bartoloni, Florence, Italy Prof Ting Wu, Xiamen University, China Jacques Izopet, Nassim Kamar & colleagues, Toulouse, France

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